(Polycyclic-arylmethoxy) indoles as inhibitors of leukotriene biosynthesis

ABSTRACT

Compounds having the formula I: ##STR1## are inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion, dysmenorrhea, and migraine.

BACKGROUND OF THE INVENTION

European Patent Applications 166,591 and 275,667 disclose a series ofindole-based compounds with activity as prostaglandin antagonists andinhibitors of leukotriene biosynthesis respectively. In EP 181,568 andEP 200,101 are disclosed a series of compounds, containing two aromaticnuclei, which are described as possessing activity as lipoxygenaseinhibitors. In EP 279,263 is disclosed a series of indoles, benzofuransand benzothiophenes which are described as possessing activity aslipoxygenase inhibitors. U.S. Pat. No. 4,629,733 describes novelindolinones which are antithrombotic and inhibit both phosphodiesteraseand tumor metastasis. The chemical preparation of quinolylindoles isreferred to by Sheinkman, et al., Chem. Ab., Vol. 67, 54017 (1967),without mentioning any utility for such compounds. A number of N-acylderivatives of indole-3-acetic acid are described as potentialanti-inflammatory agents by Biniecki, et al., Chem. Ab., Vol. 98, 197936(1983), by Pakula, et al., Chem. Ab., Vol. 105, 190835 (1986), and inBritish Pat. Spec. 1,228,848.

EP 419,049 Mar. 27, 1991) teaches (quinolin-2-ylmethoxy)indoles asinhibitors of leukotriene biosynthesis.

SUMMARY OF THE INVENTION

The present invention relates to compounds having activity asleukotriene biosynthesis inhibitors, to methods for their preparation,and to methods and pharmaceutical formulations for using these compoundsin mammals (especially humans).

Because of their activity as leukotriene biosynthesis inhibitors, thecompounds of the present invention are useful as anti-asthmatic,anti-allergic, and anti-inflammatory agents and are useful in treatingallergic rhinitis and chronic bronchitis and for amelioration of skindiseases like psoriasis and atopic eczema. These compounds are alsouseful to inhibit the pathologic actions of leukotrienes on thecardiovascular and vascular systems for example, actions such as resultin angina or endotoxin shock. The compounds of the present invention areuseful in the treatment of inflammatory and allergic diseases of theeye, including allergic conjunctivitis. The compounds are also useful ascytoprotective agents and for the treatment of migraine headache.

Thus, the compounds of the present invention may also be used to treator prevent mammalian (especially, human) disease states such as erosivegastritis; erosive esophagitis; inflammatory bowel disease;ethanol-induced hemorrhagic erosions; hepatic ischemia; noxiousagent-induced damage or necrosis of hepatic, pancreatic, renal, ormyocardial tissue; liver parenchymal damage caused by hepatoxic agentssuch as CCl₄ and D-galactosamine; ischemic renal failure;disease-induced hepatic damage; bile salt induced pancreatic or gastricdamage; trauma- or stress-induced cell damage; and glycerol-inducedrenal failure.

The compounds of this invention are inhibitors of the biosynthesis of5-lipoxygenase metabolites of arachidonic acid, such as 5-HPETE, 5-HETEand the leukotrienes. Leukotrienes B₄, C₄, D₄ and E₄ are known tocontribute to various disease conditions such as asthma, psoriasis,pain, ulcers and systemic anaphylaxis. Thus inhibition of the synthesisof such compounds will alleviate these and other leukotriene-relateddisease states.

DETAILED DESCRIPTION OF THE INVENTION ##STR2## wherein: Het is ArR¹ R² ;

Ar is a bicyclic or tricyclic aromatic hydrocarbon;

R¹, R², R³, R⁴ and R¹⁰ are independently hydrogen, halogen, perhalolower alkenyl, lower alkyl, lower alkenyl, lower alkynyl, --CF₃, --CN,--NO₂, --N₃, --C(OH)R¹¹ R¹¹, --CO₂ R¹², --SR¹⁴, --S(O)R¹⁴, --S(O)₂ R¹⁴,--S(O)₂ NR¹⁵ R¹⁵, --OR¹⁵, --NR¹⁵ R¹⁵, --NR¹² CONR¹⁵ R¹⁵, --COR¹⁶, CONR¹⁵R¹⁵, or --(CH₂)_(t) R²¹ ;

R⁵ is hydrogen, --CH₃, CF₃, --C(O)H, X¹ --R⁶ or X² --R⁷ ;

R⁶ and R⁹ are independently alkyl, alkenyl, --(CH₂)_(u) Ph(R¹⁰)₂ or--(CH₂)_(u) Th(R¹⁰)₂ ;

R⁷ is --CF₃ or R⁶ ;

R⁸ is hydrogen or X³ --R⁹ ;

each R¹¹ is independently hydrogen or lower alkyl, or two R¹¹ 's on samecarbon atom are joined to form a cycloalkyl ring of 3 to 6 carbon atoms;

R¹² is hydrogen, lower alkyl or --CH₂ R²¹ ;

R¹³ is lower alkyl or --(CH₂)_(r) R²¹ ;

R¹⁴ is --CF₃ or R¹³ ;

R¹⁵ is hydrogen, --COR¹⁶, R¹³, or two R¹⁵ 's on the same nitrogen may bejoined to form a monocyclic heterocyclic ring of 4 to 6 atoms containingup to 2 heteroatoms chosen from O, S, or N;

R¹⁶ is hydrogen, --CF₃, lower alkyl, lower alkenyl, lower alkynyl or--(CH₂)_(r) R²¹ ;

R¹⁷ is --(CH₂)_(s) --C(R¹⁸ R¹⁸)--(CH₂)_(s) --R¹⁹ or --CH₂ CONR¹⁵ R¹⁵ ;

R¹⁸ is hydrogen or lower alkyl;

R¹⁹ is

a) a monocyclic or bicyclic heterocyclic ring containing from 3 to 9nuclear carbon atoms and 1 or 2 nuclear hetero-atoms selected from N, Sor O and with each ring in the heterocyclic radical being formed of 5 or6 atoms, or

b) the radical W--R²⁰ ;

R²⁰ is alkyl or --COR²³ ;

R²¹ is phenyl substituted with 1 or 2 R²² groups;

R²² is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio,lower alkylsulfonyl, lower alkylcarbonyl, --CF₃, --CN, --NO₂ or --N₃ ;

R²³ is alkyl, cycloalkyl, or monocyclic monoheterocyclic ring;

R²⁴ is the residual structure of a standard amino acid, or R¹⁸ and R²⁴attached to the same N can cyclize to form a proline residue;

m is 0 or 1;

n is 0 to 3;

p is 1 to 3 when m is 1;

p is 0 to 3 when m is 0;

r is 0 to 2;

s is 0 to 3;

t is 0 to 2;

u is 0 to 3;

W is 0, S or NR¹⁵ ;

X¹ is 0 or NR¹⁵ ;

X² is CO, CR¹¹ R¹¹, S, S(O), or S(0)₂ ;

X³ is CO, CR¹¹ R¹¹, S(0)₂, or a bond;

X⁴ is CH═CH, CH₂ --Y¹, or Y¹ --CH₂ ;

Y is X¹ or X² ;

Y¹ is O, S, S(0)₂, or CH₂ ;

Q is --CO₂ R¹², --CONHS(O)₂ R¹⁴, --NHS(O)₂ R¹⁴, --S(O)₂ NHR¹⁵, --CONR¹⁵R¹⁵, --CO₂ R¹⁷, --CONR¹⁸ R²⁴, --CR¹¹ R¹¹ OH, or 1H- or 2H-tetrazol-5-yl;

or a pharmaceutically acceptable salt thereof.

A preferred embodiment of Formula I is that in which X⁴ is CH₂ --Y¹, Y¹is O, and the remaining sustituents are as defined for Formula I.

Another preferred embodiment of Formula I is that in which

R¹, R², R³, and R⁴ are hydrogen;

R⁵ is X² --R⁷ ;

R⁷ is R⁶ ;

R⁸ is R⁹ ;

R¹⁰ is hydrogen or halogen;

m is 0;

n is 1 to 3;

u is 0 in R⁶ and 1 in R⁹ ;

X² is CR¹¹ R¹¹ or S;

X⁴ is CH₂ --Y¹ ;

Y¹ is O;

Q is --CO₂ R¹² or 1-H or 2H-tetrazol-5-yl;

and the remaining substituents are as defined for Formula I;

or a pharmaceutically acceptable salt thereof.

DEFINITIONS

The following abbreviations have the indicated meanings:

Me=methyl

Bn=benzyl

Ph=phenyl

DIBAL-N=diisobutyl alumnium hydride

HMPA=hexamethylphosphorictriamide

KHMDS=potassium hexamethyldisilazide

t-Bu=tert-butyl

i-Pr=isopropyl

c-C₆ H₁₁ =cyclohexyl

c-Pr=cyclopropyl

c-=cyclo

Ac=acetyl

Tz=1H- or 2H- tetrazol-5-yl

Th=2- or 3-thienyl

c-C₅ H₉ =cyclopentyl

1-Ad=1-adamantyl

NBS=N-bromosuccinimide

NCS=N-chlorosuccinimide

Alkyl, alkenyl, and alkynyl are intended to include linear, branched,and cyclic structures and combinations thereof.

"Alkyl" includes "lower alkyl" and extends to cover carbon fragmentshaving up to 20 carbon atoms. Examples of alkyl groups include octyl,nonyl, norbornyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl,eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclododecyl,adamantyl, and the like.

"Lower alkyl" means alkyl groups of from 1 to 7 carbon atoms. Examplesof lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,sec-and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopropyl,cyclopropylmethyl, and the like.

"Cycloalkyl" refers to a hydrocarbon ring having from 3 to 7 carbonatoms. Examples of cycloalkyl groups are cyclopropyl, cyclopentyl,cycloheptyl, and the like.

"Lower alkenyl" means alkenyl groups of 2 to 7 carbon atoms. Examples oflower alkenyl groups include vinyl, allyl, isopropenyl, pentenyl,hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

"Lower alkynyl" means alkynyl groups of 2 to 7 carbon atoms. Examples oflower alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl,2-heptynyl, and the like.

"Lower alkoxy" means alkoxy groups of from 1 to 7 carbon atoms of astraight, branched, or cyclic configuration. Examples of lower alkoxygroups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy,cyclohexyloxy, and the like.

"Lower alkylthio" means alkylthio groups of from 1 to 7 carbon atoms ofa straight, branched or cyclic configuration. Examples of loweralkylthio groups include methylthio, propylthio, isopropylthio,cycloheptylthio, etc. By way of illustration, the propylthio groupsignifies --SCH₂ CH₂ CH₃.

The term "monocyclic monoheterocyclic ring" which defines R²³ meansmonocyclic groups of 5 to 7 members containing only 1 heteroatomselected from N, S or O in the ring. Examples include tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperidine, tetrahydropyran, and thelike.

The term "monocyclic or bicyclic heterocyclic ring" which defines R¹⁹may be 2,5-dioxo-1-pyrrolidinyl, (3-pyridinylcarbonyl) amino,1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, 1,3-dihydro-2H-isoindol-2-yl,2,4-imidazolinedion-1-yl, 2,6-piperidinedion-1-yl, 2-imidazolyl,2-oxo-1,3-dioxolen-4-yl, piperidin-1-yl, morpholin-1-yl, piperazin-1-yl,and the like.

"Bicyclic or tricyclic aromatic hydrocarbon, which defines "Ar", mayinclude naphthalene, anthracene, phenanthrene, and the like.

The point of attachment of any heterocyclic ring may be at any freevalence of the ring.

The term standard amino acid is employed to include the following aminoacids: alanine, asparagine, aspartic acid, arginine, cysteine, glutamicacid, glutamine, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine and valine. (See F. H. C. Crick, Symposium of the Society forExperimental Biology, 1958 (12) p. 140.)

It is understood that R¹ and R² may be located at any free positions ofAr.

The terms Ph(R¹⁰)₂ and Th(R¹⁰)₂ indicate a phenyl or thienyl groupsubstituted with two R¹⁰ substituents.

Halogen includes F, Cl, Br, and I.

It is intended that the definitions of any substituent (e.g., R¹, R²,R¹⁵, Ph(R¹⁰)₂, etc.) in a particular molecule be independent of itsdefinitions elsewhere in the molecule. Thus, --NR¹⁵ R¹⁵ represents--NHH, --NHCH₃, --NHC₆ H₅, etc.

The monocyclic heterocyclic rings formed when two R¹⁵ groups jointhrough N include pyrrolidine, piperidine, morpholine, thiamorpholine,piperazine, and N-methylpiperazine.

The prodrug esters of Q (i.e., when Q=CO₂ R¹⁷) are intended to includethe esters such as are described by Saari et al., J. Med. Chem., 21, No.8, 746-753 (1978), Sakamoto et al., Chem. Pharm. Bull., 32, No. 6,2241-2248 (1984) and Bundgaard et al., J. Med. Chem., 30, No. 3, 451-454(1987).

Some of the compounds described herein contain one or more asymmetriccenters and may thus give rise to diastereomers and optical isomers. Thepresent invention is meant to comprehend such possible diastereomers aswell as their racemic and resolved, enantiomerically pure forms andpharmaceutically acceptable salts thereof.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt, thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium andsodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N¹ -dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and thelike. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric and tartaric acids.

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula I are meant toalso include the pharmaceutically acceptable salts.

The ability of the compounds of Formula I to inhibit biosynthesis of theleukotrienes makes them useful for inhibiting the symptoms induced bythe leukotrienes in a human subject. This inhibition of the mammalianbiosynthesis of leukotrienes indicates that the compounds andpharmaceutical compositions thereof are useful to treat, prevent orameliorate in mammals and especially in humans: 1) pulmonary conditionsincluding diseases such as asthma, 2) allergies and allergic reactionssuch as allergic rhinitis, contact dermatitis, allergic conjunctivitis,and the like, 3) inflammation such as arthritis or inflammatory boweldisease, 4) pain, 5) skin conditions such as psoriasis and the like, 6)cardiovascular conditions such as angina, endotoxin shock, and the likeand 7) renal insufficiency arising from ischaemia induced byimmunological or chemical (cyclosporin) etiology, and that the compoundsare cytoprotective agents.

The cytoprotective activity of a compound may be observed in bothanimals and man by noting the increased resistance of thegastrointestinal mucosa to the noxious effects of strong irritants, forexample, the ulcerogenic effects of aspirin or indomethacin. In additionto lessening the effect of non-steroidal anti-inflammatory drugs on thegastrointestinal tract, animal studies show that cytoprotectivecompounds will prevent gastric lesions induced by oral administration ofstrong acids, strong bases, ethanol, hypertonic saline solutions and thelike.

Two assays can be used to measure cytoprotective ability. These assaysare; (A) an ethanol-induced lesion assay and (B) an indomethacin-inducedulcer assay and are described in EP 140, 684.

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to the age,weight and response of the individual patient. In general, the dailydose range for anti-asthmatic, anti-allergic or anti-inflammatory useand generally, uses other than cytoprotection, lie within the range offrom about 0.001 mg to about 100 mg per kg body weight of a mammal,preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to 1mg per kg, in single or divided does. On the other hand, it may benecessary to use dosages outside these limits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range for anti-asthmatic, anti-inflammatory oranti-allergic use is from about 0.001 mg to about 25 mg (preferably from0.01 mg to about 1 mg) of a compound of Formula I per kg of body weightper day and for cytoprotective use from about 0.1 mg to about 100 mg(preferably from about 1 mg to about 100 mg and more preferably fromabout 1 mg to about 10 mg) of a compound of Formula I per kg of bodyweight per day.

In the case where an oral composition is employed, a suitable dosagerange for anti-asthmatic, anti-inflammatory or anti-allergic use is,e.g. from about 0.01 mg to about 100 mg of a compound of Formula I perkg of body weight per day, preferably from about 0.1 mg to about 10 mgper kg and for cytoprotective use from 0.1 mg to about 100 mg(preferably from about 1 mg to about 100 mg and more preferably fromabout 10 mg to about 100 mg) of a compound of Formula I per kg of bodyweight per day.

For the treatment of diseases of the eye, ophthalmic preparations forocular administration comprising 0.001-1% by weight solutions orsuspensions of the compounds of Formula I in an acceptable ophthalmicformulation may be used.

The exact amount of a compound of the Formula I to be used as acytoprotective agent will depend on, inter alia, whether it is beingadministered to heal damaged cells or to avoid future damage, on thenature of the damaged cells (e.g., gastrointestinal ulcerations vs.nephrotic necrosis), and on the nature of the causative agent. Anexample of the use of a compound of the Formula I in avoiding futuredamage would be co-administration of a compound of the Formula I with anon-steroidal anti-inflammatory drug (NSAID) that might otherwise causesuch damage (for example, indomethacin). For such use, the compound ofFormula I is administered from 30 minutes prior up to 30 minutes afteradministration of the NSAID. Preferably it is administered prior to orsimultaneously with the NSAID, (for example, in a combination dosageform).

Any suitable route of administration may be employed for providing amammal, especially a human with an effective dosage of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicbases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulisers. The compounds may also bedelivered as powders which may be formulated and the powder compositionmay be inhaled with the aid of an insufflation powder inhaler device.The preferred delivery system for inhalation is a metered doseinhalation (MDI) aerosol, which may be formulated as a suspension orsolution of Compound I in suitable propellants, such as fluorocarbons orhydrocarbons.

Suitable topical formulations of Compound I include transdermal devices,aerosols, creams, ointments, lotions, dusting powders, and the like.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient, as a powder or granules or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet may be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet contains from about 2.5 mg toabout 500 mg of the active ingredient and each cachet or capsulecontains from about 2.5 to about 500 mg of the active ingredient.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I:

    ______________________________________                                        Injectable Suspension (I.M.)                                                                         mg/ml                                                  Compound of Formula I  10                                                     Methylcellulose         5.0                                                   Tween 80                0.5                                                   Benzyl alcohol          9.0                                                   Benzalkonium chloride   1.0                                                   Water for injection                                                           to a total volume of 1 ml                                                     Tablet                 mg/tablet                                              Compound of Formula I   25                                                    Microcrystalline Cellulose                                                                           415                                                    Providone               14.0                                                  Pregelatinized Starch   43.5                                                  Magnesium Stearate      2.5                                                                          500                                                    Capsule                mg/capsule                                             Compound of Formula I   25                                                    Lactose Powder         573.5                                                  Magnesium Stearate      1.5                                                                          600                                                    Aerosol                Per canister                                           Compound of Formula I  24     mg                                              Lecithin, NF Liquid Concentrate                                                                      1.2    mg                                              Trichlorofluoromethane, NF                                                                           4.025  gm                                              Dichlorodifluoromethane, NF                                                                          12.15  gm                                              ______________________________________                                    

In addition to the compounds of Formula I, the pharmaceuticalcompositions of the present invention can also contain other activeingredients, such as cyclooxygenase inhibitors, non-steroidalanti-inflammatory drugs (NSAIDs), peripheral analgesic agents such aszomepirac difluunisal and the like. The weight ratio of the compound ofthe Formula I to the second active ingredient may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the Formula I is combined with an NSAID the weight ratio of thecompound of the Formula I to the NSAID will generally range from about1000:1 to about 1:1000, preferably about 200:1 to about 1:200.Combinations of a compound of the Formula I and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

NSAIDs can be characterized into five groups:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the oxicams; and

(5) the biphenylcarboxylic acid derivatives;

or a pharmaceutically acceptable salt thereof.

The propionic acid derivatives which may be used comprise: alminoprofen,benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,flurbiprofen, ibuprofen, indoprofen, detoprofen, miroprofen, naproxen,oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, andtioxaprofen. Structurally related propionic acid derivatives havingsimilar analgesic and anti-inflammatory properties are also intended tobe included in this group.

Thus, "propionic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs having a free--CH(CH₃)COOH or --CH₂ CH₂ COOH group (which optionally can be in theform of a pharmaceutically acceptable salt group, e.g., --CH(CH₃)COO⁻Na⁺ or --CH₂ CH₂ COO⁻ Na⁺), typically attached directly or via acarbonyl function to a ring system, preferably to an aromatic ringsystem.

The acetic acid derivatives which may be used comprise: indomethacin,which is a preferred NSAID, acematacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin andzomepirac. Structurally related acetic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

Thus, "acetic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs having a free --CH₂COOH group (which optionally can be in the form of a pharmaceuticallyacceptable salt group, e.g. --CH₂ COO⁻ Na⁺), typically attached directlyto a ring system, preferably to an aromatic or heteroaromatic ringsystem.

The fenamic acid derivatives which may be used comprise: flufenamicacid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamicacid. Structurally related fenamic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

Thus, "fenamic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs which contain the basicstructure: ##STR3## which can bear a variety of substituents and inwhich the free --COOH group can be in the form of a pharmaceuticallyacceptable salt group, e.g., --COO⁻ Na⁺.

The biphenylcarboxylic acid derivatives which can be used comprise:diflunisal and flufenisal. Structurally related biphenylcarboxylic acidderivatives having similar analgesic and anti-inflammatory propertiesare also intended to be encompassed by this group.

Thus, "biphenylcarboxylic acid derivatives" as defined herein arenon-narcotic analgesics/non-steroidal anti-inflammatory drugs whichcontain the basic structure: ##STR4## which can bear a variety ofsubstituents and in which the free --COOH group can be in the form of apharmaceutically acceptable salt group, e.g., --COO⁻ Na⁺.

The oxicams which can be used in the present invention comprise:isoxicam, piroxicam, sudoxicam and tenoxican. Structurally relatedoxicams having similar analgesic and anti-inflammatory properties arealso intended to be encompassed by this group.

Thus, "oxicams" as defined herein are non narcoticanalgesics/non-steroidal anti-inflammatory drugs which have the generalformula: ##STR5## wherein R is an aryl or heteroaryl ring system.

The following NSAIDs may also be used: amfenac sodium, aminoprofen,anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydanine,beprozin, broperamole, bufezolac, cinmetacin, ciproquazone, cloximate,dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen, diacerein,di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam,epirizole, etersalate, etodolac, etofenamate, fanetizole mesylate,fenclorac, fendosal, fenflumizole, feprazone, floctafenine, flunixin,flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen,glucametacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen,isoxicam, lefetamine HCl, leflunomide, lofemizole, lonazolac calcium,lotifazole, loxoprofen, lysin clonixinate, meclofenamate sodium,meseclazone, nabumetone, nictindole, nimesulide, orpanoxin, oxametacin,oxapadol, perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac,pirfenidone, proglumetacin maleate, proquazone, pyridoxiprofen,sudoxicam, talmetacin, talniflumate, tenoxicam, thiazolinobutazone,thielavin B, tiaramide HCl, tiflamizole, timegadine, tolpadol, tryptamidand ufenamate.

The following NSAIDs, designated by company code number (see e.g.,Pharmaprojects), may also be used: 480156S, AA861, AD1590, AFP802,AFP860, AI77B, AP504, AU8001, BPPC, BW540C, CHINOIN 127, CN100, EB382,EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4, LA2851, MR714, MR897,MY309, ONO3144, PR823, PV102, PV108, R830, RS2131, SCR152, SH440,SIR133, SPAS510, SQ27239, ST281, SY6001, TA60, TAI-901(4-benzoyl-1-indancarboxylic acid), TVX2706, U60257, UR2301, andWY41770.

Finally, NSAIDs which may also be used include the salicylates,specifically acetyl salicylic acid and the phenylbutazones, andpharmaceutically acceptable salts thereof.

In addition to indomethacin, other preferred NSAIDS are acetyl salicylicacid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen,ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac and tolmetin.

Pharmaceutical compositions comprising the Formula I compounds may alsocontain inhibitors of the biosynthesis of the leukotrienes such as aredisclosed in EP 138,481 (Apr. 24, 1985), EP 115,394 (Aug. 8, 1984), EP136,893 (Apr. 10, 1985), and EP 140,709 (May 8, 1985), which are herebyincorporated herein by reference.

The compounds of the Formula I may also be used in combination withleukotriene antagonists such as those disclosed in EP 106,565 (Apr. 25,1984) and EP 104,885 (Apr. 4, 1984) which are hereby incorporated hereinby reference and others known in the art such as those disclosed in EPApplication Nos. 56,172 (Jul. 21, 1982) and 61,800 (Jun. 10, 1982); andin U.K. Patent Specification No. 2,058,785 (Apr. 15, 1981), which arehereby incorporated herein by reference.

Pharmaceutical compositions comprising the Formula I compounds may alsocontain as the second active ingredient, prostaglandin antagonists suchas those disclosed in EP 11,067 (May 28, 1980) or thromboxaneantagonists such as those disclosed in U.S. Pat. No. 4,237,160. They mayalso contain histidine decarboxylase inhibitors such asα-fluoromethylhistidine, described in U.S. Pat. No. 4,325,961. Thecompounds of the Formula I may also be advantageously combined with anH₁ or H₂ -receptor antagonist, such as for instance acetamazole,aminothiadiazoles disclosed in EP 40,696 (Dec. 2, 1981), benadryl,cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine,terfenadine and like compounds, such as those disclosed in U.S. Pat.Nos. 4,283,408; 4,362,736; and 4,394,508. The pharmaceuticalcompositions may also contain a K⁺ /H⁺ ATPase inhibitor such asomeprazole, disclosed in U.S. Pat. No. 4,255,431, and the like.Compounds of Formula I may also be usefully combined with most cellstabilizing agents, such as1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane and related compoundsdescribed in British Patent Specifications 1,144,905 and 1,144,906.Another useful pharmaceutical composition comprises the Formula Icompounds in combination with serotonin antagonists such asmethysergide, the serotonin antagonists described in Nature, Vol. 316,pages 126-131, 1985, and the like. Each of the references to in thisparagraph is hereby incorporated herein by reference.

Other advantageous pharmaceutical compositions comprise the Formula Icompounds in combination with anti-cholinergics such as ipratropiumbromide, bronchodilators such as the beta agonist salbutamol,metaproterenol, terbutaline, fenoterol and the like, and theanti-asthmatic drugs theophylline, choline theophyllinate andenprofylline, the calcium antagonists nifedipine, diltiazem,nitrendipine, verapamil, nimodipine, felodipine, etc. and thecorticosteroids, hydrocortisone, methylprednisolone, betamethasone,dexamethasone, beclomethasone, and the like.

Compounds of the present invention can be prepared according to thefollowing methods. Temperatures are in degrees Celsius.

The starting methoxy phenylhydrazines II are either commerciallyavailable or are described in the chemical literature as are theacetamidophenols XXVI. The benzyl phenylhydrazine starting materials IIIare prepared as described in EP 166,591 (17102 IA) and the ketones IVand XXXI are prepared as described in EP 166,591 and EP 275,667 (17496IA). The 2-(halomethyl)quinolines VII are available from literaturemethods described in "Quinolines" Parts I and II, G. Jones (ED.), JohnWiley & Sons, Toronto, 1977 and 1982. The preparation of VII byhalogenation of the corresponding 2-methylquinolines is also describedin the Jones' volumes. The benzyl halides, (R¹⁰)₂ PhCH₂ -Hal, arereadily prepared and many such compounds are described in the prior art,such as U.S. Pat. No. 4,808,608 (17323 IB). Hal in VII and (R¹⁰)₂ PhCH₂-Hal represents Cl, Br or I.

Many syntheses of indoles are well-known in the chemical literature: seefor example, "Heterocyclic compounds" Volume 25, Parts I, II, III, W. J.Houlihan (Ed.), Interscience, J. Wiley & Sons, N.Y., 1979, and "TheChemistry of Indoles" by R. J. Sundberg, Academic Press, N.Y., 1970. Oneof the most common sytheses is known as the Fischer Indole Synthesis,and is abbreviated in the following methods as "Fishcher".

The --CO₂ H and --CO₂ R¹² groups in the intermediates and final productsin the various methods can be transformed to other representatives of Qsuch as --CONHS(O)₂ R¹⁴, --NHS(O)₂ R¹⁴, --CONR¹⁵ R¹⁵, --CH₂ OH ortetrazol-5-yl by the methodology described in U.S. Pat. No. 4,808,608(17323IB). The preparation of the pro-drug forms (Q is --CO₂ R¹⁷) fromthe acids may be effected by the methodology of EP 104,885 (16830 IA).

It will be apparent to one skilled in the art that the variousfunctional groups (R¹, R², Y, Q, etc.) must be chosen so as to becompatible with the chemistry being carried out. Such compatibility canoften be achieved by protecting groups, or by specific variations in thesequence of the reactions.

When R⁵ is S--R⁷, the corresponding sulfoxides and sulfones can beprepared by oxidation of the sulfides with one or two equivalents of anoxidizing agent such as m-chloroperbenzoic acid or monoperoxyphthalicacid or oxone (Trost, J. Org. Chem., 1988, pg. 532).

Many of the following methods involve a basic hydrolysis of an esterfunction to obtain the corresponding carboxylic acid. In all cases, thefree acid is obtained by acidification of the reaction mixture with asuitable acid such as hydrochloric, sulfuric, acetic, trifluoroaceticacid, etc.

Compounds 6, 10, 11, 16, 17, 19, 23, 24, 27, 28, and their precursoresters are all examples of the Formula I compounds of the presentinvention.

Compounds identified by Roman numerals (IV, V, XIV, XXVI, XXXI, andXXXV) are known and correspond to those compounds in EP 419,049, whichis incorporated herein by reference. ##STR6##

METHOD 1

The carboxy derivative 1 may be reduced by a suitable hydride reducingagent such as lithium aluminum hydride, sodium borohydride, DIBAL-H, orthe like in appropriate solvents such as ether, THF, hexane, toluene, ormixtures thereof, to obtain alcohol 2. The alcohol function of 2 can beconverted to a suitable leaving group (LG) such as a halide, or asulfonate ester (mesylate, tosylate, triflate, etc.) by methods wellknown in the art to produce intermediate 3. A useful subgroup of 3 canbe prepared by halogenation of the methyl compound Het-CH₃ by heatingwith halogenating agents such as NCS or NBS in appropriate solvents suchas carbon tetrachloride, benzene, and the like.

Reaction of 3 with triphenylphosphine in ether, acetonitrile, THF, orsimilar solvents produces the phosphonium salt 4. Compound 4 isconverted into the ylid 5 by treating with a base such as Et₃ N, sodiumhydride, butyl lithium, or an alkoxide, depending upon the reactivity ofthe phosphonium salt 4.

METHOD 2

Compound 3 is reacted with phenol XIV, in the presence of a suitablebase such as potassium or cesium carbonate in a suitable solvent such asacetone, acetonitrile, or DMF to yield compound 6 which can be convertedto its corresponding carboxylic acid by standard procedures. ##STR7##

METHOD 3

A suitable N-acetylated aminophenol XXVI is reacted with 3 using analkali hydride or carbonate, such as potassium carbonate as a base in apolar solvent like DMF or NMP. The resulting acetanilide 7 is thende-acetylated using standard basic conditions, preferably usingalcoholic potassium hydroxide under reflux to produce the anilinederivative 8. Conversion of the aniline derivative to the hydrazineanalogue 9 is effected through reduction of the intermediate diazoniumsalt using sodium hydrosulfite in an aqueous medium.

The hydrazine 9 is then processed using a Fischer indolization withketone IV to produce compound 10, which is then alkylated on the indolenitrogen using R⁸ -Hal and a suitable base such as KHMDS in THF or NaHin DMF to give compound 11. ##STR8##

METHOD 4

Indole phenol XIV is transformed to a phenol triflate 12 by treatmentwith trifluoromethyl sulfonic anhydride (Tf₂ O) in a solvent likepyridine in dichloromethane. The phenol triflate may becarboxymethylated to a compound like 13 under palladium acetatecatalysis in an atmosphere of carbon monoxide, a phosphine ligand like1,1-bis(diphenylphosphinoferrocene) enhances this reaction. Reduction ofthe carboxymethylated indole may be effected with a variety of hydridereducing agents. Conveniently, DIBAL-H is used in THF on the hydrolysedester. The reduced carbinol product 14 is conveniently oxidized to aformylated derivative 15 with manganese dioxide in methylene chloride asa typical solvent. Aldehyde 15 can then be homologated under carbanionconditions, typically using Wittig reagent 5 as shown in the method,under anydrous conditions in an etherial solvent like THF. Thetemperature of this reaction is typically from -70° C. to roomtemperature. Indole styryl analogues (trans) 16 are thus formed. Furthertransformation of the styryl system may be effected by catalyticreduction using H₂ and Pd/C in an organic solvent like ethyl acetate toyield the saturated compound 17. ##STR9##

METHOD 5

Indole thio analogues of I such as 23 and 24 are conveniently preparedby the sequence shown in Method 5. The treatment of compound V with BBr₃in a chlorinated solvent such as CH₂ Cl₂ cleaves both the methyl etherand the indole N-benzyl group and cyclizes the product to an indolelactam 18. Derivatization of this compound as anN,N-dimethylthiocarbamoyl indole 19 followed by thermal rearrangementat >200° C. gives rise to an N,N-dimethylcarbamoylthioindole derivative20. Depending on the duration of heating, dethiolation (R⁵ ═--S-t-Bu→R⁵═H) may also take place. The hydrolysis of 20 may be effected usingstrong base, typically sodium methoxide in methanol is used. Spontaneousformation of disulfide 21 may occur in this reaction. The reduction of21 can be achieved using triphenylphosphine in aqeuous dioxane toproduce 22. Coupling of 22 to an appropriately substituted derivative 3takes place under organic base catalysis. Typically triethylamine, in anorganic solvent such as methylene chloride, is used. Transformation ofindole 23 to an N-substituted derivative 24 is achieved under standardconditions described in Method 3. ##STR10##

METHOD 6

Hydrazine 9 may also be transformed directly to unsubstituted indoles bya Fischer reaction with various ketones like XXXI. N-Alkylation of theindoles is effected using the conditions described in Method 3 toproduce hetmethoxyindole alkanoate esters 25. Such esters aretransformed to ketones or carbinols via Grignard conditions using alkylmagnesium halides in ether solvents like diethyl ether or through theuse of lithium aluminum hydride in ether solvents like THF. thecarbinols 27 so produced may be further transformed into ester compoundsof the present invention by reacting with halo esters XXXV using sodiumhydride as base in a suitable solvent like THF. Subsequent hydrolysis ofthe esters leads to acid compounds 28 of the present invention.##STR11##

METHOD 7

The preparation of the various definitions of Q is outlined in Method 7,starting from the readily available carboxylic acid derivative --CO₂R¹². It will be obvious to one skilled in the art that many of thereactions indicated are reversible. Thus, by way of illustration, the--CN group can serve as the starting material to prepare the amide andcarboxylic acid functional groups. The reactions depicted in Method 7,as well as methods for synthesis of the sulfonamide group (--S(O)₂NHR¹⁵), are well-known in the art. See, for instance, the followingtextbooks:

1. J. March, Advanced Organic Chemistry, 3rd ed., J. Wiley and Sons,Toronto, 1985;

2. S. R. Sandler and W. Karo, Organic Functional Group Preparations, I &II, Academic Press, Toronto, 1983 and 1986.

REPRESENTATIVE COMPOUNDS

Table I illustrates compounds representative of the present invention.

                                      TABLE I                                     __________________________________________________________________________     ##STR12##                                                                    Ex.                                                                           No.                                                                              R.sup.1 /R.sup.2                                                                  Ar       X.sup.4                                                                            R.sup.5                                                                              R.sup.8                                                                              Y(CR.sup.11 R.sup.11).sub.pQ               __________________________________________________________________________    1  H/H naphth-2-yl                                                                            CH.sub.2 O                                                                         Me     CH.sub.2 Ph-4-Cl                                                                     C(Me).sub.2 CO.sub.2 H                     2  H/H anthracen-2-yl                                                                         CH.sub.2 S                                                                         S-t-Bu CH.sub.2 Ph-4-Cl                                                                     C(Me).sub.2 CO.sub.2 H                     3  H/H phenanthren-3-yl                                                                       CH.sub.2 CH.sub.2                                                                  COCH.sub.2 -t-Bu                                                                     CH.sub.2 Ph-3-CN                                                                      ##STR13##                                 __________________________________________________________________________

ASSAYS FOR DETERMINING BIOLOGICAL ACTIVITY

Compounds of Formula I can be tested using the following assays todetermine their mammalian leukotriene biosynthesis inhibiting activity.

Rat Peritoneal Polymorphonuclear (PMN) Leukocyte Assay

Rats under ether anesthesia are injected (i.p.) with 8 mL of asuspension of sodium caseinate (6 grams in ca. 50 mL water). After 15-24hr. the rats are sacrificed (CO₂) and the cells from the peritonealcavity are recovered by lavage with 20 mL of buffer (Eagles MEMcontaining 30 mM HEPES adjusted to pH 7.4 with NaOH). The cells arepelleted (350×g, 5 min.), resuspended in buffer with vigorous shaking,filtered through lens paper, recentrifuged and finally suspended inbuffer at a concentration of 10 cells/mL. A 500 mL aliquot of PMNsuspension and test compound are preincubated for 2 minutes at 37° C.,followed by the addition of 10 mM A-23187. The suspension is stirred foran additional 4 minutes then bioassayed for LTB₄ content by adding analiquot to a second 500 mL portion of the PMN at 37° C. The LTB₄produced in the first incubation causes aggregation of the second PMN,which is measured as a change in light transmission. The size of theassay aliquot is chosen to give a submaximal transmission change(usually -70%) for the untreated control. The percentage inhibition ofLTB₄ formation is calcuated form the ratio of transmission change in thesample to the transmission change in the compound-free control.

Human Polymorphonuclear (PMN) Leukocyte LTB₄ Assay

A. Preparation of Human PMN. Human blood is obtained by antecubitalvenepuncture from consenting volunteers who have not taken medicationwithin the previous 7 days. The blood is immediately added to 10% (v/v)trisodium citrate (0.13M) or 5% (v/v) sodium heparin (1000 IU/mL). PMNsare isolated from anticoagulated blood by dextran sedimentation oferythrocytes followed by centrifugation through Ficoll-Hypaque (specificgravity 1.077), as described by Boyum (Scand. J. Clin. Lab. Invest., 21(Supp. 97), 77(1968)). Contaminating erythrocytes are removed by lysisfollowing exposure to ammonium chloride (0.16M) in Tris buffer (pH7.65), and the PMNs resuspended at 5×10⁵ cells/mL in HEPES (15mM)-buffered Hanks balanced salt solution containing Ca²⁺ (1.4 mM) andMg²⁺ (0.7 mM), pH 7.4. Viability is assessed by Trypan blue exclusion.

B. Generation and Radioimmunoassay of LTB₄. PMNs (0.5 mL; 2.5×10⁵ cells)are placed in plastic tubes and incubated (37° C., 2 min) with testcompounds at the desired concentration or vehicle (DMSO, finalconcentration 0.2%) as control. The synthesis of LTB₄ is initiated bythe addition of calcium ionophore A23187 (final concentration 10 mM) orvehicle in control samples and allowed to proceed for 5 minutes at 37°C. The reactions are then terminated by the addition of cold methanol(0.25 mL) and samples of the entire PMN reaction mixture removed forradioimmunoassay of LTB₄.

Samples (50 mL) of authentic LTB₄ of known concentration inradioimmunoassay buffer (RIA) buffer (potassium phosphate 1 mM; disodiumEDTA 0.1 mM; Thimerosal 0.025 mM; gelatin 0.1%, pH 7.3) or PMN reactionmixture diluted 1:1 with RIA buffer are added to reaction tubes.Thereafter, [³ H]-LTB₄ (10 nCi in 100 mL RIA buffer) and LTB₄ -antiserum(100 mL of a 1:3000 dilution in RIA buffer) are added and the tubesvortexed. Reactants are allowed to equilibrate by incubation overnightat 4° C. To separate antibody-bound from free LTB₄, aliquots (50 mL) ofactivated charcoal (3% activated charcoal in RIA buffer containing 0.25%Dextran T-70) are added, the tubes vortexed, and allowed to stand atroom temperature for 10 minutes prior to centrifugation (1500×g; 10 min;4° C.). The supernatants containing antibody-bound LTB₄ are decantedinto vials and Aquasol 2 (4 mL) added. Radioactivity is quantified byliquid scintillation spectrometry. The specificity of the antiserum andthe sensitivity of the procedure have been described by Rokach et al.(Prostaglandins Leukotrienes and Medicine, 1984, 13, 21.) The amount ofLTB₄ produced in test and control (approx. 20 ng/10⁶ cells) samples iscalculated. Inhibitory dose-response curves are constructed using afour-parameter algorithm and from these the IC₅₀ values are determined.

Asthmatic Rat Assay

Rats are obtained from an inbred line of asthmatic rats. Both female(190-250 g) and male (260-400 g) rats are used.

Egg albumin (EA), grade V, crystallized and lyophilized, is obtainedfrom Sigma Chemical Co., St. Louis. Aluminum hydroxide is obtained fromthe Regis Chemical Company, Chicago. Methysergide bimaleate is suppliedby Sandoz Ltd., Basel.

The challenge and subsequent respiratory recordings are carried out in aclear plastic box with internal dimensions 10×6×4 inches. The top of thebox is removable; in use, it is held firmly in place by four clamps andan airtight seal is maintained by a soft rubber gasket. Through thecenter of each end of the chamber a DeVilbiss nebulizer (No. 40) isinserted via an airtight seal and each end of the box also has anoutlet. A Fleisch No. 0000 pneumotachograph is inserted into one end ofthe box and coupled to a Grass volumetric pressure transducer (PT5-A)which is then connected to a Beckman Type R Dynograph throughappropriate couplers. While aerosolizing the antigen, the outlets areopen and the pneumotachograph is isolated from the chamber. The outletsare closed and the pneumotachograph and the chamber are connected duringthe recording of the respiratory patterns. For challenge, 2 mL of a 3%solution of antigen in saline is placed into each nebulizer and theaerosol is generated with air from a small Potter diaphragm pumpoperating at 10 psi and a flow of 8 liters/minute.

Rats are sensitized by injecting (subcutaneously) 1 mL of a suspensioncontaining 1 mg EA and 200 mg aluminum hydroxide in saline. They areused between days 12 and 24 postsensitization. In order to eliminate theserotonin component of the response, rats are pretreated intravenously 5minutes prior to aerosol challenge with 3.0 mgm/kg of methysergide. Ratsare then exposed to an aerosol of 3% EA in saline for exactly 1 minute,then their respiratory profiles are recorded for a further 30 minutes.The duration of continuous dyspnea is measured from the respiratoryrecordings.

Compounds are generally administered either orally 1-4 hours prior tochallenge or intravenously 2 minutes prior to challenge. They are eitherdissolved in saline or 1% methocel or suspended in 1% methocel. Thevolume injected is 1 mL/kg (intravenously) or 10 mL/kg (orally). Priorto oral treatment rats are starved overnight. Their activity isdetermined in terms of their ability to decrease the duration ofsymptoms of dyspnea in comparison with a group of vehicle-treatedcontrols. Usually, a compound is evaluated at a series of doses and anED₅₀ is determined. This is defined as the dose (mg/kg) which wouldinhibit the duration of symptoms by 50%.

The invention is further defined by reference to the following examples,which are intended to be illustrative and not limiting. All temperaturesare in degrees Celsius.

INTERMEDIATES Preparation 1: Methyl3-[1-(4-chlorobenzyl)-3-methyl-5-hydroxy-indol-2-yl]-2,2-dimethylpropanoat

To a solution of 1.05 g (2.7 mmol) of3-[1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl]-2,2-dimethylpropanoicacid (EP 166,591, Example 22) and 800 μL of ethanethiol (10 mmol) in 20mL of CH₂ Cl₂ at -20° C. was added in portions 2.17 g (16 mmol) ofAlCl₃. The reaction turned light orange and was stirred at roomtemperature overnight. In the morning, the reaction was completed (tlc)and it was poured into a solution of 1N HCl and extracted 3× with CH₂Cl₂. The combined organic layers were washed with brine, dried (MgSO₄),and filtered. The filtrate was evaporated and to the residual syrup (680mg) was added 20 mL of Et₂ O followed by an ethereal solution ofdiazomethane. Evaporation of the solvent left the crude title compoundwhich was used without further purification.

¹ H NMR (250 MHz, CDCl₃): δ 7.3-7.15 (m, 3H, aromatic); 6.96 (m, 1H,aromatic): 6.70 (m, 3H, aromatic); 5.34 (s, 2H, N--CH₂); 4.8-4.5 (M, 1H,--OH); 3.76 (s, 3H, --CO₂ Me); 3.12 (s, 2H, 2-CH₂); 2.40 (S, 3H, 3-Me);1.44 (s, 6H, C(Me)₂).

Preparation 2: Methyl3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate

The title compound was prepared as described in EP 419,049, Example 1,Step C.

Preparation 3:3-[1-(4-Chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoicacid

To a mixture of LiH (12.6 g) and HMPA (105 mL) in DMF (1050 mL) at 0° C.was added 2-methyl-2-propanethiol (178 mL). The mixture was stirred atroom temperature for 30 min, then3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropanoicacid methyl ester (150 g) (EP 419,049, Example 1, Step A) in DMF (450mL) was added slowly. The mixture was slowly heated to 150° C. and keptat that temperature for 18 hours. After cooling to room temperature, thesupernatant layer was decanted and the residue dissolved in H₂ O andacidifed with 1N HCl, extracted twice with Et₂ O, washed twice withbrine, dried over MgSO₄, filtered and evaporated to dryness to providethe title compound.

Preparation 4:3-[1-(4-Chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoicacid allyl ester

The compound from Preparation 3 (150 g) was dissolved in DMF (1.2 L)then the solution was cooled in an ice-water bath. To this solution wasadded K₂ CO₃ (138 g) portionwise and the mixture was left to stir for 30min. Then allyl bromide (162 g) was added, the ice bath removed, and themixture stirred for 18 hours. To the mixture was added aqueous NH₄ Cland it was extracted with Et₂ O. The organic layer was washed with H₂ Oand brine, dried over MgSO₄, filtered, and evaporated to dryness.Purification by silica gel chromatography afforded the title compound;m.p. 150°-151° C.

EXAMPLE 13-[1-(4-Chlorobenzyl)-3-methyl-5-(naphth-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoicacid Step 1: Methyl3-[1-(4-chlorobenzyl)-3-methyl-5-(naphth-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoicacid

A solution of methyl3-[1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate(Preparation 1) (200 mg), 2-bromomethynaphthalene (138 mg), K₂ CO₃ (89mg), and Cs₂ CO₃ (34 mg) in 5 mL DMF was stirred at room temperatureunder nitrogen for 24 hours. The mixture was poured onto 1N HCl,extracted 2× EtOAc, washed 2× brine, dried (MgSO₄), and evaporated.Purification of the residue by chromatography (silica gel; hexane/EtOAc4:1) gave the title compound, used as such for the next step.

Step 2:3-[1-(4-Chlorobenzyl)-3-methyl-5-(naphth-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoicacid

A solution of the ester from Step 1 (278 mg), 3 mL THF, 3 mL MeOH, and2.7 mL 1N LiOH was stirred at 80° C. for 4 hours under nitrogen. Thesolution was cooled, poured onto 1N HCl, extracted 2× EtOAc, washed 2×brine, dried (MgSO₄), and evaporated. Purification of the residue bychromatography (silica gel; hexane/EtOAc 2:1) gave the title compound asa solid, m.p. 151.5°-152.5° C.

What is claimed is:
 1. A compund of the formula I: ##STR14## wherein:Het is ArR¹ R² ;Ar is a bicyclic or tricyclic aromatic hydrocarbon; R¹,R², R³, R⁴ and R¹⁰ are independently hydrogen, halogen, perhalo loweralkenyl, lower alkyl, lower alkenyl, lower alkynyl, --CF₃, --CN, --NO₂,--N₃, --C(OH)R¹¹ R¹¹, --CO₂ R¹², --SR¹⁴, --S(O)R¹⁴, --S(O)₂ R¹⁴, --S(O)₂NR¹⁵ R¹⁵, --OR¹⁵, --NR¹⁵ R¹⁵, --NR¹² CONR¹⁵ R¹⁵, --COR¹⁶, CONR¹⁵ R¹⁵, or--(CH₂)_(t) R²¹ ; R⁵ is hydrogen, --CH₃, CF₃, --C(O)H, X¹ --R⁶ or X²--R⁷ ; R⁶ and R⁹ are independently alkyl, alkenyl, --(CH₂)_(u) Ph(R¹⁰)₂or --(CH₂)_(u) Th(R¹⁰)₂, wherein Ph is phenyl and Th is 2- or 3-thienyl;R⁷ is --CF₃ or R⁶ ; R⁸ is hydrogen or X³ --R⁹ ; each R¹¹ isindependently hydrogen or lower alkyl, or two R¹¹ 's on same carbon atomare joined to form a cycloalkyl ring of 3 to 6 carbon atoms; R¹² ishydrogen, lower alkyl or --CH₂ R²¹ ; R¹³ is lower alkyl or --(CH₂)_(r)R²¹ ; R¹⁴ is --CF₃ or R¹³ ; R¹⁵ is hydrogen, --COR¹⁶, R¹³, or two R¹⁵ 'son the same nitrogen may be joined to form a monocyclic heterocyclicring of 4 to 6 atoms containing up to 2 heteroatoms chosen from O, S, orN; R¹⁶ is hydrogen, --CF₃, lower alkyl, lower alkenyl, lower alkynyl or--(CH₂)_(r) R²¹ ; R¹⁷ is --(CH₂)_(s) --C(R¹⁸ R¹⁸)--(CH₂)_(s) --R¹⁹ or--CH₂ CONR¹⁵ R¹⁵ ; R¹⁸ is hydrogen or lower alkyl; R¹⁹ isa)2,5-dioxy-1-pyrrolidinyl, (3-pyridinylcarbonyl) amino,1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, 1,3-dihydro-2H-isoindol-2-yl,2,4-imidazolinedion-1-yl, 2,6-piperidinedion-1-yl, 2-imidazolyl,2-oxo-1,3-dioxolen-4-yl, piperidin-1-yl, morpholin-1-yl, orpiperazin-1-yl, or b) the radical W--R²⁰ ; R²⁰ is alkyl or --COR²³ ; R²¹is phenyl substituted with 1 or 2 R²² groups; R²² is hydrogen, halogen,lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, loweralkylcarbonyl, --CF₃, --CN, --NO₂ or --N₃ ; R²³ is alkyl, cycloalkyl, ormonocyclic monoheterocyclic ring of 5 to 7 members containing only 1heteratom selected from N, S, or O; R²⁴ is the residual structure of astandard amino acid, or R¹⁸ and R²⁴ attached to the same N can cyclizeto form a proline residue; m is 0 or 1; n is 0 to 3; p is 1 to 3 when mis 1; p is 0 to 3 when m is 0; r is 0 to 2; s is 0 to 3; t is 0 to 2; uis 0 to 3; W is 0, S or NR¹⁵ ; X¹ is O or NR¹⁵ ; X² is CO, CR¹¹ R¹¹, S,S(O), or S(0)₂ ; X³ is CO, CR¹¹ R¹¹, S(0)₂, or a bond; X⁴ is CH═CH, CH₂--Y¹, or Y¹ --CH₂ ; Y is X¹ or X² ; Y¹ is O, S, S(0)₂, or CH₂ ; Q is--CO₂ R¹², --CONHS(O)₂ R¹⁴, --NHS(O)₂ R¹⁴, --S(O)₂ NHR¹⁵, --CONR¹⁵ R¹⁵,--CO₂ R¹⁷, --CONR¹⁸ R²⁴, --CR¹¹ R¹¹ OH, or 1H- or 2H-tetrazol-5-yl;or apharmaceutically acceptable salt thereof.
 2. A compound of claim 1whereinX⁴ is CH₂ --Y¹ and Y¹ is O;or a pharmaceutically acceptable saltthereof.
 3. A compound of claim 1 wherein:R¹, R², R³, and R⁴ arehydrogen; R⁵ is X² --R⁷ ; R⁷ is R⁶ ; R⁸ is R⁹ ; R¹⁰ is hydrogen orhalogen; m is 0; n is 1 to 3; u is 0 in R⁶ and 1 in R⁹ ; X² is CR¹¹ R¹¹or S; X⁴ is CH₂ --Y¹ ; Y¹ is O; and Q is --CO₂ R¹² ;or apharmaceutically acceptable salt thereof.
 4. The compound of claim 1wherein:R¹, R², R³, and R⁴ are hydrogen; R⁵ is X² --R⁷ ; R⁷ is R⁶ ; R⁸is R⁹ ; R¹⁰ is hydrogen or halogen; m is 0; n is 1 to 3; u is 0 in R⁶and 1 in R⁹ ; X² is CR¹¹ R¹¹ or S; X⁴ is CH₂ --Y¹ ; Y¹ is 0; and Q is1-H- or 2H-tetrazol-5-yl;or a pharmaceutically acceptable salt thereof.5. A compound of claim 1 of the formula Ia: ##STR15## wherein thesubstituents are as follows:

    __________________________________________________________________________    Ex.                                                                           No.                                                                              R.sup.1 /R.sup.2                                                                  Ar       X.sup.4                                                                            R.sup.5                                                                              R.sup.8                                                                              Y(CR.sup.11 R.sup.11).sub.p -Q             __________________________________________________________________________    1  H/H naphth-2-yl                                                                            CH.sub.2 O                                                                         Me     CH.sub.2 Ph-4-Cl                                                                     C(Me).sub.2 CO.sub.2 H                     2  H/H anthracen-2-yl                                                                         CH.sub.2 S                                                                         S-t-Bu CH.sub.2 Ph-4-Cl                                                                     C(Me).sub.2 CO.sub.2 H                     3  H/H phenanthren-3-yl                                                                       CH.sub.2 CH.sub.2                                                                  COCH.sub.2 -t-Bu                                                                     CH.sub.2 Ph-3-CN                                                                      ##STR16##                                 __________________________________________________________________________


6. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 and a pharmaceutically acceptablecarrier.
 7. A pharmaceutical composition of claim 6 additionallycomprising an effective amount of a second active ingredient selectedfrom the group consisting of non-steroidal anti-inflammatory drugs;peripheral analgesic agents; cyclooxygenase inhibitors; leukotrieneantagonists; leukotriene biosynthesis inhibitors; H₂ -receptorantagonists; antihistaminic agents; prostaglandin antagonists;thromboxane antagonists; thromboxane synthetase inhibitors; and ACEantagonists.
 8. A pharmaceutical composition of claim 7, wherein thesecond active ingredient is a non-steroidal anti-inflammatory drug.
 9. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1, an effective amount of a second activeingredient which is a non-steroidal anti inflammatory drug, and apharmaceutically acceptable carrier, wherein the weight ratio of saidcompound of claim 1 to said second active ingredient ranges from about1000:1 to 1:1000.
 10. A method of preventing the synthesis, the action,or the release of SRS-A or leukotrienes in a mammal which comprisesadministering to said mammal an effective amount of a compound ofclaim
 1. 11. A method of claim 10 wherein the mammal is man.
 12. Amethod of treating asthma in a mammal comprising administering to amammal in need of such treatment a therapeutically effective amount of acompound of claim
 1. 13. A method of treating inflammatory diseases ofthe eye in a mammal which comprises administering to a mammal in need ofsuch treatment a therapeutically effective amount of a compound ofclaim
 1. 14. The method of claim 13 wherein the mammal is man.